ABSTRACT Temporal lobe epilepsy (TLE) develops after a period of ongoing molecular cascades and neural circuit remodeling in the hippocampus resulting in increased susceptibility to spontaneous seizures. Targeting these cascades in TLE patients could reverse their symptoms and have the potential to provide a viable disease- modifying treatment, especially for the large portion of over 30% of TLE patients who do not respond to any available treatments. In recent years, the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has been implicated in temporal lobe epilepsy (TLE). The JAK/STAT pathway is known to be involved in inflammation and immunity, and only more recently has been shown to be associated with neuronal functions such as synaptic plasticity. Our laboratories previously showed that a JAK inhibitor, WP1066, could greatly reduce the number of spontaneous seizures that animals went on to develop over time in the pilocarpine model of status epilepticus (SE). We have continued to investigate the mechanism of JAK/STAT- induced epileptogenic responses through the use of a new transgenic line we developed where STAT3 knockdown (KD) can be controlled by tamoxifen-induced CRE expression specifically in forebrain excitatory neurons via the Calcium/Calmodulin Dependent Protein Kinase II alpha (CamK2a) promoter. We now report that this knockdown of STAT3 (nSTAT3KD) markedly reduces spontaneous seizure frequency in the intrahippocampal kainate model (IHKA) and ?rescues? mice from KA-induced memory deficits as measured by Contextual Fear Conditioning. Recently, using deep RNA-sequencing we also discovered transcriptomic signatures 24 hours after SE that occur in response to IHKA injections (ipsilateral and contralateral to the injection site) and are reversed by nSTAT3KD, especially for those genes important in sphingolipid metabolism: a regulator of neuronal structure, and the trafficking, stability, and function of multiple membrane bound receptors, including ligand- and voltage-gated ion channels. These findings, taken together with our preliminary IHKA metabolome, brings us to propose the following unique hypothesis that there is a JAKx/STAT3 pathway in excitatory forebrain neurons that becomes activated in response to prolonged seizures and that identifying the cells most susceptible to STAT3 signaling during the epileptogenic process will provide a window on basic circuitry that underlies memory formation, and most importantly, the brain's susceptibility to epilepsy development. To test this hypothesis, we have three Aims using state of the art molecular technologies (metabolomic profiling, single nuclei RNA sequencing, and chromatin immunoprecipitation sequencing) to interrogate the molecular signature of the hippocampus (24 h, 2 wk, and 4 wk after IHKA SE) . The emerging transcriptome for STAT3 in the context of epilepsy suggests that it may be useful for identifying potential epileptogenic gene networks that were previously unknown, selecting early-detection biomarkers that inform seizure susceptibility, as well as choosing new targets for the future treatment of intractable epilepsies.